Diabetes is a disease characterized by failure of insulin feedback and secretion in the beta cells of the pancreatic islets of Langerhans and is one of the most common endocrine diseases across all age groups and populations. The most obvious metabolic effect in diabetes is chronic, erratic elevation of the blood glucose level which is associated with progressive damage to blood vessels. This may lead to heart attack, stroke, blindness, peripheral nerve dysfunction, and kidney failure. Presently there are 18.2 million people in the United States alone who have diabetes. In addition to the clinical morbidity and mortality, the economic cost of diabetes is huge, exceeding $90 billion per year in the United States alone, and the prevalence of diabetes is expected to increase.
There are two major forms of diabetes mellitus: insulin-dependent (Type I) diabetes mellitus which accounts for 5 to 10% of all cases, and non-insulin-dependent (Type-II) diabetes mellitus which comprises roughly 90 to 95% of cases.
Type I diabetes mellitus is an autoimmune disease characterized by progressive destruction of pancreatic beta-cells and most often occurring in children and young adults. The disease is associated with high rate of severe irreversible complications which occur despite the availability of insulin replacement, usually through injections administered 1-4 times daily.
Most therapeutic strategies for treatment or prevention of type I diabetes mellitus are directed to suppression of the autoimmune response in order to prevent beta-cell destruction. Accordingly, various immunosuppressive agents have been considered for preventing destruction of pancreatic beta-cells have been attempted, such as glucocorticoids, cyclophosphamide, cyclosporin A, rapamycin, FK506 and prodigiosin. However, the use of such immunosuppressive agents may cause severe side effects such as drug-related toxicity to liver or kidney and to increase incidence of infectious complications, particularly in patients with diabetes mellitus that are already susceptible to infections as part of their disease.
Type-II diabetes results from a loss of insulin production combined with body's inability to properly use insulin (insulin resistance), and is oftentimes associated with obesity and aging. In Type II diabetes, patients typically begin therapy by following a regimen of an optimal diet, weight reduction and exercise. Drug therapy is initiated when these measures no longer provide adequate metabolic control. Initial drug therapy includes: sulfonylureas (for example, tolbutamide, chlorpropamide and glibenclamide), biguanides (for example, metformin and buformin) and a-glucosidase inhibitors (for example, acarbose and voglibose). However, over 50% of all diabetics treated by presently available drugs demonstrate poor glycemic control within six years, and require insulin replacement therapy as the last resort.
Although many of the symptoms of diabetes mellitus may be controlled by insulin therapy, the long-term complications of both type I and type II diabetes mellitus are severe and may reduce life expectancy by as much as one third. Over time, elevated blood glucose levels damage blood vessels, the heart, eyes, kidneys, nerves, autonomic nervous system, skin, connective tissue, and white blood cell function.
Moreover, insulin therapy may result in insulin allergy, insulin resistance, atrophy of the subcutaneous fat at the site of insulin injection (i. e., lipoatrophy), enlargement of subcutaneous fat deposit (i. e., lipohypertrophy) due to lipogenic action of high local concentration of insulin, and insulin edema.
There is thus a widely recognized need for, and it would be highly advantageous to have new, safe and effective therapies for diabetes mellitus.